Guidance for IndustryEnvironmental Assessment of HumanDrug and Biologics Applications

U.S. Department of Health and Human ServicesFood and Drug Administration

Center for Drug Evaluation and Research (CDER)Center for Biologics Evaluation and Research (CBER)

July 1998CMC 6

Revision 1

Guidance for IndustryEnvironmental Assessment of HumanDrug and Biologics Applications

Copies of this guidance are available from the Office of Training and Communications,Division of Communications Management, Drug Information Branch, HFD-210, 5600 FishersLane, Rockville, MD 20857 (Phone 301-827-4573) or from the Internet athttp://www.fda.gov/cder/guidance/index.htm.

Copies also are available from the Office of Communication, Training and ManufacturersAssistance, HFM-40, CBER, FDA, 1401 Rockville Pike, Rockville, MD 20852-1448, or from theInternet at http://www.fda.gov/cber/guidelines.htm. Copies also may be obtained by fax from 1-888-CBERFAX or 301-827-3844 or from Voice Information at 800-835-4709 or 301-827-1800.

U.S. Department of Health and Human Services

Food and Drug AdministrationCenter for Drug Evaluation and Research (CDER)

Center for Biologics Evaluation and Research (CBER)July 1998

CMC 6Revision 1

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TABLE OF CONTENTS

I. INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

II. WHAT TYPES OF ACTIONS ARE SUBJECT TO CATEGORICALEXCLUSION? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2

III. WHEN IS AN EA REQUIRED? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3A. NDAs, Abbreviated Applications, and Supplements . . . . . . . . . . . . . . . . . . . 3B. Applications for Substances that Occur Naturally in the Environment . . . . 5C. Extraordinary Circumstances . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

IV. PREPARING AN EA FOR SUBMISSION TO CDER or CBER . . . . . . . . . . . . . . . 9A. Content and Format . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9B. Specific Guidance — Environmental Issues . . . . . . . . . . . . . . . . . . . . . . . . . 13C. Data Summary Table . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26D. Test Methods and Report Formats . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26E. Confidential and Nonconfidential Information . . . . . . . . . . . . . . . . . . . . . . . 26F. Master Files for Drugs and Biologics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27

REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28

ATTACHMENT A: NO INCREASED USE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29

ATTACHMENT B: INCREASED USE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30

ATTACHMENT C: 40 CFR 1508.27 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31

ATTACHMENT D: EA FORMAT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32

ATTACHMENT E: SAMPLE DATA SUMMARY TABLE . . . . . . . . . . . . . . . . . . . . . . . 33

ATTACHMENT F: CONFIDENTIAL/NONCONFIDENTIAL . . . . . . . . . . . . . . . . . . . . 34

ATTACHMENT G: GLOSSARY OF TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37

This guidance has been prepared under the direction of the Chemistry Manufacturing Controls Coordinating1

Committee, Center for Drug Evaluation and Research (CDER), and the Center for Biologics Evaluation and Research(CBER) at the Food and Drug Administration. This guidance represents the Agency's current thinking on environmentalassessments. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. An alternative approach may be used if such approach satisfies the requirements of the applicable statute, regulations, orboth.

GUIDANCE FOR INDUSTRY 1

Environmental Assessment of Human Drug and Biologics Applications

I. INTRODUCTION

The National Environmental Policy Act of 1969 (NEPA) requires all Federal agencies to assessthe environmental impacts of their actions and to ensure that the interested and affected public isinformed of environmental analyses. The Food and Drug Administration (FDA) is required underNEPA to consider the environmental impacts of approving drug and biologics applications as anintegral part of its regulatory process. FDA's regulations in 21 CFR part 25 specify thatenvironmental assessments (EAs) must be submitted as part of certain new drug applications(NDAs), abbreviated applications, applications for marketing approval of a biologic product,supplements to such applications, investigational new drug applications (INDs) and for variousother actions (see 21 CFR 25.20), unless the action qualifies for categorical exclusion.

Under the President's reinventing government (REGO) initiatives, announced in April 1995, FDAreevaluated and revised its environmental regulations to reduce the number of EAs required to besubmitted by industry and, consequently, the number of findings of no significant impact(FONSIs) prepared by the Agency under NEPA. FDA issued for public comment a notice ofproposed rulemaking on April 3, 1996 (61 FR 14922) (republished May 1, 1996 (61 FR 19476)),that proposed additional categorical exclusions for those actions that have been identified asnormally not having a significant effect, individually or cumulatively, on the quality of the humanenvironment. The final rule was published on July 29, 1997 (62 FR 40569), and became effectiveAugust 28, 1997. All applications or petitions requesting Agency action (e.g., NDAs, abbreviatednew drug applications (ANDAs), INDs, biologics license applications (BLAs), supplements tosuch applications) must be accompanied by either an EA or a claim of categorical exclusion. Failure to provide (1) a claim of categorical exclusion or (2) an adequate EA, is sufficient groundsfor refusing to file or approve the application (21 CFR 314.101(d)(4), 601.2(a) and (c), and25.15(a)). An EA that is adequate for filing is one that addresses the relevant environmentalissues. An EA adequate for approval is one that contains sufficient information to enable theAgency to determine whether the proposed action may affect significantly the quality of thehuman environment. This guidance provides information on when an EA should be submitted; italso makes recommendations on how to prepare EAs for submission of drug or biologicsapplications to the Center for Drug Evaluation and Research (CDER) and the Center for

Regulations would require an EIS (environmental impact statement) when "evaluation of data or information2

in an EA or otherwise available to the agency leads to a finding by the responsible agency official that a proposed actionmay significantly affect the quality of the human environment (21 CFR 25.22(b)).

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Biologics Evaluation and Research (CBER). Topics covered include (1) when categoricalexclusions apply, (2) when to submit an EA, (3) the content and format of EAs, (4) specificguidance for the environmental issues that are most likely to be associated with human drugs andbiologics, (5) test methods, (6) an applicant's treatment of confidential information submitted insupport of an EA, and (7) master files for drugs and biologics.

This guidance, which is based on the July 1997 final rule, will remain in effect until superseded bynew regulations or new guidance. The guidance is intended to supersede CDER's Guidance forIndustry For the Submission of an Environmental Assessment in Human Drug Applications andSupplements, which was published in November 1995. Information in this guidance, along withinformation in the Code of Federal Regulations (CFR) at 21 CFR part 25 and 40 CFR parts 1500-1508 and the FDA Environmental Assessment Technical Handbook (NTIS Publication NumberPB 87 175345/AS), which provides information on acceptable test methods, represents the coreinformation available from CDER and CBER to assist industry in preparing an EA.

II. WHAT TYPES OF ACTIONS ARE SUBJECT TO CATEGORICALEXCLUSION?

Certain classes of actions are subject to categorical exclusion and, therefore, ordinarily do notrequire the preparation of an EA because, as a class, these actions, individually or cumulatively,do not significantly affect the quality of the human environment (21 CFR 25.5(c)). However, asrequired under 21 CFR 25.21 and 40 CFR 1508.4, FDA will require "at least an EA" for anyspecific action that ordinarily would be excluded if extraordinary circumstances indicate that thespecific proposed action may significantly affect the quality of the human environment. See2

section III.C for additional information regarding extraordinary circumstances.

Submissions to CDER or CBER that ordinarily are excluded categorically under the regulationsinclude actions on (1) NDAs, abbreviated applications, applications for marketing approval of abiologic product, and supplements to such applications if FDA's approval of the application doesnot increase the use of the active moiety; (2) NDAs, abbreviated applications, and supplements tosuch applications if FDA's approval of the application increases the use of the active moiety, butthe estimated concentration of the substance at the point of entry into the aquatic environmentwill be below 1 part per billion (ppb); (3) NDAs, abbreviated applications, applications formarketing approval of a biologic product, and supplements to such applications for substancesthat occur naturally in the environment when the approval of the application does not altersignificantly the concentration or distribution of the substance, its metabolites, or degradationproducts in the environment; (4) INDs; and (5) applications for marketing approval of a biologicproduct for transfusable human blood or blood components and plasma. An applicant is eligible

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to file a claim of categorical exclusion from the requirement to submit an EA if the action meetsthe criteria of at least one categorical exclusion.

A person submitting an application or petition of a type subject to categorical exclusion under 21CFR 25.31 is not required to submit an EA if the person states that the action requested qualifiesfor categorical exclusion, citing the particular categorical exclusion that is claimed, and states thatto the applicant’s knowledge, no extraordinary circumstances exist (21 CFR 25.15(d)). Anapplicant ordinarily need not provide data to demonstrate that the action qualifies for categoricalexclusion. CDER and CBER can rely on other information submitted in an application toevaluate the appropriateness of a claim for categorical exclusion. In the limited instances when itmay be necessary, CDER or CBER will request additional information as needed to establish totheir satisfaction that the criteria for categorical exclusion have been met.

III. WHEN IS AN EA REQUIRED?

Preparation of an environmental assessment ordinarily is required unless the proposed actionqualifies for an exclusion under 21 CFR 25.30 or 25.31. An EA would also be required ifextraordinary circumstances indicate that the specific proposed action may significantly affect thequality of the human environment (21 CFR 25.21).

Detailed information is provided below for the most common situations when actions would notqualify for categorical exclusion.

A. NDAs, Abbreviated Applications, and Supplements

Note: Section 1, below, should be used to assess increased use of a biological product asreferenced in 21 CFR 25.31(a). Section 2 does not apply to biologics license applications(BLAs) because BLAs are not included in the categorical exclusion on which this sectionis based (21 CFR 25.31(b)). BLAs should be evaluated for whether they are eligible forcategorical exclusion using 21 CFR 25.31(a) or (c) or other appropriate categoricalexclusions found in 21 CFR 25.30 and 25.31.

NDAs, abbreviated applications, and supplements to such applications would not qualifyfor categorical exclusion if FDA's approval of the application increases the use of theactive moiety and the estimated concentration of the substance at the point of entry intothe aquatic environment will be 1 ppb or greater.

1. Increased Use

Increased use of an active moiety may occur if the drug will be administered athigher dosage levels, for longer duration, or for different indications than werepreviously in effect, or if the drug is a new molecular entity. The term use alsoencompasses disposal of FDA-regulated articles by consumers.

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Attachment A contains examples of actions that would not be considered toincrease the use of a drug and Attachment B contains examples of actions thatwould be considered to increase the use of a drug or biologic. These lists are notinclusive. An applicant is encouraged to contact the appropriate Center if anyquestions arise as to whether a particular action is considered to increase the use ofa drug or biologic.

2. Estimating the Concentration of a Substance at the Point of Entry into theAquatic Environment

The expected introduction concentration (EIC) of an active moiety into the aquaticenvironment should be calculated as follows:

EIC-Aquatic (ppb) = A x B x C x D where

A = kg/year produced for direct use (as active moiety)B = 1/liters per day entering POTWs*C = year/365 daysD = 10 µg/kg (conversion factor)9

* 1.214 x 10 liters per day entering publicly owned treatment works (POTWs),11

Source: 1996 Needs Survey, Report to Congress. Information regarding the NeedsSurvey is available on the Internet at http://www.epa.gov/owm. It is updatedperiodically.

This calculation assumes:

! All drug products produced in a year are used and enter the publicly ownedtreatment works (POTW) system.

! Drug product usage occurs throughout the United States in proportion tothe population and amount of waste water generated.

! There is no metabolism.

The estimate of the kilogram/year active moiety should be based on or include (1)the highest quantity of the active moiety expected to be produced for direct use inany of the next five years. Produced for direct use means the quantity intended foruse in humans during a given year (i.e., excludes any quantity produced forinventory buildup), (2) the quantity used in all dosage forms and strengths includedin the application, and (3) the quantity used in an applicant's related applications. Related applications include those for other dosage forms using the same activemoiety and for products using different forms of the active moiety (e.g., level ofhydration, salt, free acid/base). All concentrations should be reported as the

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concentration of active moiety, rather than the salt or complex.

The calculation of the expected introduction concentration (EIC) of an activemoiety entering into the aquatic environment from patient use can consider theextent of metabolism of the active moiety to less pharmacologically active orinactive compounds, if that information is available. The pharmacological activityof metabolites relative to the active moiety should be considered when calculatingthe EIC. The weighted contribution of the metabolite to the EIC should becalculated (e.g., kg/year active moiety x 10% x 0.5 for a metabolite found at a level of 10% and that has half the pharmacological activity of the active moiety). If the pharmacological activity of the metabolite is unknown, it can be assumed tobe the same as the active moiety.

An alternative calculation should be used if the drug product is intended for use ina specific geographic location (e.g., use an alternative value for the amount ofliters per day entering POTWs — term B in the EIC calculation above). Moreover, if an alternative calculation is used to estimate localized use, or for anyother reason, the calculation and the source and basis for the alternative calculationshould be provided when filing an EA or a claim of categorical exclusion andwould be subject to review.

B. Applications for Substances that Occur Naturally in the Environment

NDAs, abbreviated applications, applications for marketing approval of a biologic productand supplements to such applications for substances that occur naturally in theenvironment would not qualify for categorical exclusion under 21 CFR 25.31(c) whenFDA's approval of the application alters significantly the concentration or distribution ofthe substance, its metabolites, or degradation products in the environment. This might bethe case when the use and disposal occur in a geographic area where the substance doesnot naturally occur. However, the application may be eligible for a categorical exclusionunder other provisions in 21 CFR 25.31.

In addition to drug and biologic products derived from natural sources or from biologicalsystems, substances can be considered naturally occurring even if they are chemicallysynthesized. The Agency will consider the form in which the FDA-regulated article willexist in the environment when determining whether the drug or biologic is a naturallyoccurring substance. For example, a modified active moiety (e.g., salt) that does notoccur naturally could be considered a naturally occurring substance if it is established that,in vivo and in the environment, the active moiety exists in a form that is found naturally.

Biological and biotechnological products will be similarly evaluated. For example, aprotein or DNA comprising naturally occurring amino acids or nucleosides, but having asequence different from that of a naturally occurring substance, will normally qualify as a

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naturally occurring substance after consideration of metabolism. The same principlewould apply to synthetic peptides and oligonucleotides and living and dead cells andorganisms. CDER and CBER may rely on other information submitted in an application(e.g., information about metabolism, excretion, and stability; viability (if applicable); andphysical and/or chemical characteristics of the product) in determining whether the FDA-regulated article would be considered a naturally occurring substance.

CDER and CBER will evaluate on a case-by-case basis the appropriateness of categoricalexclusions claiming that the quantity of the naturally occurring substance that is expectedto enter the environment as a result of an action will not alter significantly theconcentration or distribution of the substance, its metabolites, or degradation products inthe environment.

C. Extraordinary Circumstances

As stated in 21 CFR 25.21 and 40 CFR 1508.4, FDA will require at least an EA for anyspecific action that ordinarily would be categorically excluded if extraordinarycircumstances indicate that the specific proposed action could significantly affect thequality of the human environment. Extraordinary circumstance can be shown by dataavailable either to the Agency or the applicant and can be based on the production, use, ordisposal from use of the FDA-regulated article. Data available to the Agency can includepublic information, information submitted in the application, and data available to theAgency on the same or similar products.

1. Actions for which available data establish that there is a potential forserious harm to the environment at the expected level of exposure.

FDA considers harm to the environment to include not only toxicity toenvironmental organisms but also environmental effects other than toxicity, such aslasting effects on ecological community dynamics.

2. Actions that adversely affect a species or the critical habitat of a speciesdetermined under the Endangered Species Act or the Convention onInternational Trade in Endangered Species of Wild Fauna and Flora to beendangered or threatened, or wild fauna or flora that are entitled to specialprotection under some other Federal law.

Actions that adversely affect a species or the critical habitat of a speciesdetermined under the Endangered Species Act to be endangered or threatened,wild fauna or flora listed in the Convention on International Trade in EndangeredSpecies of Wild Fauna and Flora (CITES), or wild fauna or flora that are entitledto special protection under some other Federal law or international treaty to whichthe United States is a party would be considered an extraordinary circumstance,and an EA should be submitted unless there are specific exemptions relating to the

FDA may clarify the environmental information that must be submitted to the Agency in marketing3

applications for specific drug or biologic products derived from plants or animals (e.g., paclitaxel, 61 FR 58694).

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pharmaceutical substances or FDA action. An example of an exception would bewhen a species is afforded special protection under Federal law or internationaltreaty, but the pharmaceutical is derived only from nonwild specimens. If nonwildspecimens are exempted from Federal law or treaty, the action would be eligiblefor categorical exclusion as indicated in section III.C.3.a. Both direct effects (e.g.,pharmaceuticals derived from fauna or flora, see section III.C.3) and indirecteffects (e.g., adverse effects from manufacturing site emissions) should beconsidered.

Under the U.S. Endangered Species Act (ESA), Congress declared, "[T]he UnitedStates has pledged itself as a sovereign state in the international community toconserve to the extent practicable the various species of fish or wildlife and plantsfacing extinction, pursuant to the Convention on International Trade inEndangered Species of Wild Fauna and Flora" (16 U.S.C. 1531(a)(4)(F)). Identification as an endangered or threatened species does not preclude the use ofsuch fauna or flora. However, under the ESA, if a species has been determined tobe endangered or threatened, a Federal agency is required to consult with theSecretary of Interior or the Secretary of Commerce to ensure that the agency'sactions are not likely to jeopardize the continued existence of endangered orthreatened species or their critical habitats (16 U.S.C. 1536).

3. Use of Fauna or Flora

FDA intends to examine closely the proposed actions for FDA-regulated articlesobtained from fauna and flora and will use the extraordinary circumstancesprovision to require an EA in any instance in which it appears from an examinationof the proposed action that the action may jeopardize the continued existence of aspecies. The following sections discuss CDER's and CBER's current position onwhen the use of fauna or flora normally would constitute an extraordinarycircumstance for which an EA should be submitted to support the application.3

a. Cultivated Specimens

Actions involving drug or biologic products derived from cultivated plants(e.g., plantation, nursery stock) or bred or domestic animals (e.g.,laboratory breed, cows, pigs) are not normally considered an extraordinarycircumstance that would require an EA for an action that is normallycategorically excluded (see section III.C.2 for a possible exception).

b. Wild Specimens

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i. NDAs, abbreviated applications, applications for marketingapproval of a biologic product, or certain supplements tosuch applications.

NDAs, abbreviated applications and applications for marketingapproval of a biologic product where the drug or biologic productis derived from plants or animals taken from the wild, supplementsto such applications that relate to changes in the source of the wildbiomass (e.g., species, geographic region where biomass isobtained), or supplements to such applications that are consideredto increase the use of an active moiety or biologic substance (seeAttachment B) and which will cause more harvesting than what wasdescribed in the original EA would be considered an extraordinarycircumstance, and an EA should be submitted.

ii. INDs

INDs generally involve relatively small quantities of a drug orbiologic product and treatment of a limited number of patients. Many INDs never result in the filing of an NDA or application formarketing approval of a biologic product, which would allow forthe wide-spread commercial sale of the product. CDER and CBERwill evaluate INDs on a case-by-case basis where the drug orbiologic product is derived from wild plants or animals to determinewhether the extraordinary circumstance provision in 21 CFR 25.21is invoked.

To facilitate Center review, when submitting a claim of categoricalexclusion for actions where the drug or biologic product is derived fromplants or animals, CDER and CBER request that the applicant provide thefollowing information with the claim, or specifically identify where theinformation can be located (e.g., page number of application): (1)biological identification (i.e., common names, synonyms, variety, species,genus and family); (2) a statement as to whether wild or cultivatedspecimens are used; (3) the geographic region (e.g., country, state,province) where the biomass is obtained; and (4) a statement indicatingwhether the species is (a) determined under the Endangered Species Act orthe Convention on International Trade in Endangered Species of WildFauna and Flora (CITES) to be endangered or threatened, (b) entitled tospecial protection under some other Federal law or international treaty towhich the United States is a party, or (c) the critical habitat of a speciesthat has been determined to be endangered or threatened under theEndangered Species Act or the Convention on International Trade inEndangered Species of Wild Fauna and Flora (CITES) or is entitled to

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special protection under some other Federal law or international treaty towhich the United States is a party. CDER and CBER will use thisinformation to evaluate whether the claim of categorical exclusion isappropriate.

4. Production and Disposal Sites

FDA has found that regulated articles produced and disposed of in compliancewith all applicable emission requirements do not significantly affect theenvironment and has determined it is unnecessary to review a company'scompliance with Federal, State, and local environmental laws. In addition, bothCDER and CBER routinely require as part of their safety evaluations that liveorganisms be inactivated following production and prior to release into theenvironment if there is a reasonable possibility that the living system may beharmful to the environment. Therefore, CDER and CBER will not routinelyrequest submission of manufacturing and disposal information in an EA. However, if information available to the Agency or the applicant establishes thatthe general or specific emission requirements promulgated by Federal, State, orlocal environmental protection agencies do not address unique emissioncircumstances and the emissions may harm the environment, this would besufficient grounds for requesting manufacturing or disposal information in an EA. Actions that threaten a violation of Federal, State, or local law or requirementsimposed for the protection of the environment may constitute a significant impact(40 CFR 1508.27(b)(10)).

5. Significant Effects as Defined in 40 CFR 1508.27

The Council on Environmental Quality has provided a definition of "significantly"to aid in determining if an action may significantly affect the quality of the humanenvironment. These examples should be considered when evaluating whetherextraordinary circumstances exist that may warrant submission of at least an EA(See Attachment C).

IV. PREPARING AN EA FOR SUBMISSION TO CDER or CBER

A. Content and Format

This section describes the basic information that should be submitted in an EA if an EA isrequired. Attachment D contains an outline of the format for an EA. Alternative formatsmay be used, but the applicant should recognize that use of a standard format, such asdescribed in this guidance, promotes efficiency in the review process.

1. Date

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The EA should include the date the EA was originally prepared and the date(s) ofany subsequent amendments.

2. Name of Applicant or Petitioner

The EA should identify the applicant who is submitting the application.

3. Address

The EA should contain the address where all correspondence is to be directed.

4. Description of Proposed Action

a. Requested Approval

The description of the requested approval should include the drug orbiologic application number (if available), the drug or biologic productname, the dosage form and strength, and a brief description of the productpackaging. For example, "XYZ Pharmaceuticals has filed an NDApursuant to section 505(b) of the Federal Food, Drug, and Cosmetic Actfor TRADE NAME (established name), 250 mg and 500 mg, packaged inOHDPE bottles. An EA has been submitted pursuant to 21 CFR part 25."

b. Need for Action

The EA should briefly describe the drug's or biologic's intended uses in thediagnosis, cure, mitigation, treatment, or prevention of disease.

c. Locations of Use

The EA should identify the location(s) where the product will be used. Depending on the type of product and its use, the locations of use aretypically identified as hospitals, clinics and/or patients in their homes. Ifuse is expected to be concentrated in a particular geographic region, thisfact should be included.

d. Disposal Sites

Unless other disposal methods by the end user are anticipated, it issufficient to state that at U.S. hospitals, pharmacies, or clinics, empty orpartially empty packages will be disposed of according to hospital,pharmacy, or clinic procedures and/or that in the home, empty or partiallyempty containers will typically be disposed of by a community's solid wastemanagement system, which may include landfills, incineration, and

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recycling, although minimal quantities of the unused drug could bedisposed of in the sewer system.

5. Identification of Substances that are the Subject the Proposed Action

The EA should contain information that allows for the accurate location of data about the substance in the scientific literature and for identification of closelyrelated compounds. At a minimum, the information listed below should beprovided, if available. For many biological products, format items 5.a.iii, b, c, andd will not apply. Other information, such as the international nonproprietary name(INN) or nonsystematic or semisystematic chemical names should be included ifdeemed useful in the identification of the compounds.

Usually this information need only be provided for the drug or biologic substance,but the same information also should be provided for the form of the activeingredient in the drug or biologic product if it is different from the drug or biologicsubstance (e.g., a salt formed in situ from a free base) or for a pharmacologicallyactive related substance formed by conversion from a pharmacologically inactiveparent compound (e.g., a prodrug product is converted to the pharmacologicallyactive form).

a. Nomenclature

i. Established Name (U.S. Adopted Name-USAN)

ii. Brand/Proprietary Name/Tradename

iii. Chemical Names or Genus/Species of Biologic Product(e.g., virus)

! Chemical Abstracts (CA) Index Name (invertedform)

! Systematic Chemical Name (uninverted form)

b. Chemical Abstracts Service (CAS) registration number

c. Molecular Formula

d. Molecular Weight

e. Structural (graphic) Formula/Amino Acid Sequence

6. Environmental Issues

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The type of information provided will vary depending on the environmental issuesassociated with the particular action. In general, the EA should include a succinctdescription of the environmental issues. The affected environment and theenvironmental effects and their significance should be discussed. Data andanalyses to support the discussions should be provided as appropriate. Specificguidance is provided in section IV.B for the environmental issues that are mostlikely to be associated with human drugs and biologics. For environmental issuesnot specifically addressed in section IV.B (e.g., those included in sections III.C.4and 5), applicants are encouraged to consult the appropriate Center prior topreparing the EA.

7. Mitigation Measures

Describe measures taken to avoid or mitigate any potential adverse environmentaleffects associated with the proposed action. If no adverse environmental effectshave been identified, it should be so stated and indicated that, therefore, nomitigation measures are needed. See section IV.B.2.b for additional informationregarding the discussion of mitigation measures for actions involving fauna andflora.

8. Alternatives to the Proposed Action

If no potential adverse environmental effects have been identified for the proposedaction, the EA should state this. If potential adverse environmental effects havebeen identified for the proposed action, the EA "shall discuss any reasonablealternative course of action that offers less environmental risk or that isenvironmentally preferable to the proposed actions" (21 CFR 25.40(a)). Thediscussion should include the no-action alternative and measures that FDA oranother government agency could undertake as well as those the applicant orpetitioner would undertake. The EA should include a description of thosealternatives that will enhance the quality of the environment and avoid some or allof the adverse environmental effects of the proposed action. The environmentalbenefits and risks of the proposed action and the environmental benefits and risksof each alternative should be discussed. See section IV.B.2.c for additionalinformation regarding the discussion of alternatives for actions involving fauna andflora.

9. List of Preparers

The EA should include the name, job title, and qualifications (e.g., educationaldegrees) of those persons preparing the assessment and should identify any personsor agencies consulted. Contract testing laboratories should be included in the listof consultants, although this may be included in a confidential appendix. Curriculum vitae can be included in lieu of a description of an individual's

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qualifications.

10. References

The EA should include a list of citations for all referenced material and standardtest methods used in generating data in support of the EA. Copies of referencedarticles that are not generally available and that are used to support specific claimsin the EA document should be attached in a nonconfidential appendix.

11. Appendices

Both confidential and nonconfidential appendices can be included. See sectionIV.E for additional information about the treatment of confidential information. Alist of the appendices should be included in the EA summary document with adesignation of confidential or nonconfidential following each of the listings. Typically, the nonconfidential appendices include data summary tables and copiesof referenced articles that are generally unavailable or that were used to support specific claims in the EA. Proprietary or confidential information, such as useestimates and test reports, should be included in the confidential appendices.

B. Specific Guidance — Environmental Issues

1. Assessing Toxicity to Environmental Organisms

If an EA is required, it normally should focus on characterizing the fate and effectsof the compound of interest in the environment (1) when FDA's approval of theapplication increases the use of an active moiety and the estimated concentrationof the active moiety at the point of entry into the aquatic environment is 1 ppb orgreater (see section III.A); (2) when the substance occurs naturally in theenvironment and FDA's approval of the application alters significantly theconcentration or distribution of the substance, its metabolites, or degradationproducts in the environment (see section III.B); or (3) in some cases, when dataavailable to the Agency or applicant establish that at the expected level ofexposure, there is the potential for serious harm to the environment (see sectionIII.C.1). The provided information should focus on the fate and effects of theactive moiety and/or structurally related substances (SRSs), rather than onexcipients, for example.

The Centers encourage the use of a logical, tiered approach to testing so thatadequate information is available to assess the potential environmental fate andeffects of pharmaceuticals while minimizing the cost to industry. Figure 1 providesan illustration of a tiered approach. Alternative, scientifically justified approachesalso can be used.

Figure 1Tiered Approach to Fate and Effects Testing

Determine environments of Potential ConcernAtmospheric, Aquatic and/or Terrestrial

Investigate DepletionMechanism(s)

MicrobialInhibition Test STOP

rapid

complete

MicrobialInhibition Test

No rapid, completedepletion mechanism

Log Kow > 3.5 Consider InitiatingChronic Toxicity Testing

Tier 3

Log Kow <3.5 or Log Kow > 3.5 with justification

TIER 1Acute Toxicity1 species

LC or EC < 100050 50

MEEC

STOP

Tier 3

No Observed Effectsat MEEC

Observed Effectsat MEEC

TIER 2Acute ToxicityBase SetAquatic &/orTerrestrial

LC or EC > 100050 50

MEEC

LC or EC > 10050 50

MEEC

STOP

Tier 3

No Observed Effectsat MEEC

Observed Effectsat MEEC

LC or EC < 10050 50

MEEC

TIER 3Chronic ToxicityAquatic &/orTerrestrial

LC or EC > 10 & No Observed Effects at MEEC50 50MEEC

STOP

LC or EC < 10 or Observed Effects at MEEC50 50

MEEC

Consult CDER/CBER

Note: MEEC = EEC or EIC whichever is greater

14

15

Information submitted for fate and effects can include specific data generated onthe test substance or relevant information on analogous compounds from thesubmitter or from peer-reviewed literature as appropriate. Actual experimentaldata regarding base parameters are generally preferable to computer modeling;however, in some circumstances computer modeling may be appropriate. FDAshould be consulted if a company believes computer modeling is appropriate andwishes to use modeling in an EA.

a. Environmental Fate of Released Substances

i. Identification of Substances of Interest

The actual substances that will enter or exist in the environment(i.e., atmospheric, aquatic, terrestrial) can include the parentcompound (i.e., drug or biologic substance) or SRSs such as thedissociated parent compound, metabolites, or degradants. The EAshould list the drug or biologic substance and the predominantSRSs expected to enter or exist in the environment; provide thename, chemical structure and CAS number when possible; andprovide a rationale for the decision as to which substance(s) will bestudied. Predominant SRSs should be considered those greaterthan 10 percent of dose.

In most cases, fate (and effects) information should be provided onthe parent (or active) drug or biologic substance, as representativeof substances entering the environment. Such information isrelevant to SRSs when the SRSs possess the same fundamentalstructure as the parent drug or biologic substance and arecomparably or more polar. At a minimum, the EA should contain adiscussion of the potential fate and effects of the predominant SRSsbased on their structural differences and/or similarities to the parentcompound (e.g., due to a functional group change, the metaboliteshould be more soluble than the parent compound, or the SRS ismore polar). Computerized structure-activity relationship modelingprograms may be useful in supporting extrapolation of fate andeffects information from the parent (or active) drug or biologicsubstance to the SRS. Relevant available pharmacologic activityand toxicity information should be provided for the SRSs. Specifictoxicity-activity information for SRSs may be included in aconfidential appendix. Additional environmental information on apredominant SRS may be warranted, following consultation withthe appropriate Center, if the fate of the compound is expected todiffer from the parent compound, or there is an indication that the

16

SRSs effect on the environment would be substantially greater thanfrom the parent drug or biologic substance.

ii. Physical and Chemical Characterization

The following tests should be conducted to determine if thecompound is most likely to amass predominantly in aquatic,terrestrial, and/or atmospheric environments:

! Water Solubility

! Dissociation Constant(s)

! Octanol/Water Partition Coefficient

! Vapor Pressure or Henry's Law Constant

If there is a scientific basis for not performing a test, thejustification should be included in the EA (e.g., water solubility wasnot determined because the compound is hydrolytically unstable). For a test compound that associates or dissociates in water, watersolubility and the octanol/water partition coefficient may have to bedetermined at pH 5 and 9 as well as pH 7.

The octanol/water partition coefficient (K ) is an indicator of aow

nonionized compound's potential to adsorb to the organic fractionof soil, sediment, or biosolids (i.e., sludge) in addition to being anindicator of a compound's lipophilicity. It is not as good a predictorfor inorganic chemicals, metal organic complexes, dissociating,ionic organic compounds, or compounds with other mitigatingstructural features such as molecular size. Further study of thesorption and/or desorption properties (K ) of a substance tooc

biosolids should be considered if log K is greater than 3 or otherow

properties indicate that sorption or desorption may occur.

iii. Environmental Depletion Mechanisms

Depletion mechanisms should be investigated to determine if thereis degradation of the compound in the environment(s) of interest. Itis usually sufficient to provide basic supporting information thatidentifies the potential for a compound to be removed from theenvironment by a depletion mechanism (e.g., photolysis orhydrolysis based on information developed for analytical methodsvalidation or from stability studies). It is unnecessary to go to

17

extraordinary effort to identify a depletion mechanism once thetypical depletion mechanisms (i.e., hydrolysis, photolysis,biodegradation) have been investigated or to continue investigatingother potential depletion mechanisms once one has been identified.

If the depletion mechanism is being used to reduce the expectedintroduction concentration or to eliminate effects testing, a formal,detailed analysis of the depletion mechanism should be provided(e.g., according to a standard test method, rate determination,analysis of expected exposure time in the environment).

Consideration should be given to the nature and extent of thedegradation. If a rapid, complete depletion mechanism is identified(degradants are relatively simple, polar by-products), no testing todetermine the environmental effects of the compound should beperformed except for a microbial inhibition test or other appropriatetest to assess the potential for the compound to disrupt wastetreatment processes. Based on the estimated time prior to emissionfrom a treatment facility, the following would be considered rapiddepletion mechanisms:

Hydrolysis t (pH 5-9): # 24 hours½

Aerobic Biodegradation t : # 8 hours½

Soil Biodegradation t : # 5 days½

Direct and indirect photolysis, although significant under laboratoryconditions, may not be as rapid a depletion mechanism in theenvironment due to significant variation in light intensity (e.g.,related to weather, latitude, depth penetration) and duration ofexposure. Efforts to characterize photolysis as a depletionmechanism should take these factors into consideration.

iv. Environmental Concentrations

Expected Introduction Concentration (EIC): The environmentalintroduction concentrations into those environments (i.e., aquatic,terrestrial, atmospheric) where the substance(s) of interest is mostlikely to amass (see section IV.B.1.a.ii) should be estimated. Amethod of calculating the expected introduction concentration of asubstance into the aquatic environment is described in sectionIII.A.2. The calculation of the expected introduction concentration(EIC) entering into the aquatic environment from patient use, inaddition to considering metabolism as described in section III.A.1, may include consideration of the environmental depletion

18

mechanisms that occur in the waste treatment process (e.g.,adsorption, degradation, hydrolysis), if the information is available(see section IV.B.1.a.iii).

Some drug or biologic substance and/or active moiety may enterthe terrestrial environment when biosolids from waste watertreatment facilities, which contain adsorbed material, are applied toland. Application of biosolids to land is subject to regulation bythe Environmental Protection Agency (EPA) or an appropriateState authority. Biosolids are generally subjected to some form ofaerobic or anaerobic digestion in the waste treatment facility. TheEIC for the terrestrial compartment should be estimated if, based onthe available physical or chemical properties of the compound,significant quantities of the active moiety are expected to adsorb tobiosolids. The calculation used will depend on the typicaltreatment, disposal, and application processes. Currently,approximately 6.8 million tons of biosolids (dry basis) are generatedper year with 54 percent of that quantity being applied to land. Theremaining biosolids are incinerated, landfilled or disposed of byother means. Depletion mechanisms (e.g., biodegradation,hydrolysis) that occur in the waste treatment process can beconsidered when calculating the EIC for the terrestrialcompartment, if the information is available. Additionalinformation regarding land application of biosolids is available fromEPA's Office of Wastewater Management (on the Internet athttp://www.epa.gov/owm/bio.htm).

The concentration expected in the atmospheric compartment neednot be routinely calculated for pharmaceutical productsadministered through inhalation because, for the majority of these,the active moiety or other compound of interest is not released intothe air. However, the EIC should be considered for products thatare released primarily into the air (e.g., medical gases).

CDER and CBER have defined use to encompass disposal of FDA-regulated articles by consumers. Normally, the EIC from disposalneed not be calculated since the majority of pharmaceuticalproducts will be totally consumed, and any residual waste willtypically be disposed of in landfills or at incineration facilities thatare regulated by the EPA or appropriate State agencies. Theseagencies have considered the environmental impacts from theoperation of these facilities in their licensing process and requirecontrols (e.g., scrubbers, lined landfills, migration tests) to limit therelease of materials into the environment. The EIC for disposal

19

should be calculated if significant quantities of material areexpected to be disposed of other than by landfill, incineration orother procedures regulated by the EPA or appropriate Stateagencies.

Expected Environmental Concentration (EEC): The expectedenvironmental concentration (EEC), sometimes referred to as thepredicted environmental concentration (PEC), is the concentrationof the active moiety or other compound of interest that organismswould be exposed to in the environment (e.g., surface water) afterconsideration of, for example, spatial or temporal concentration ordepletion factors such as dilution, degradation, sorption and/orbioaccumulation. Adjustments to the expected introductionconcentration may be made, based on spatial and temporalconcentration or depletion factors, to provide an expectedenvironmental concentration. Supporting information and/ordiscussion should be provided to explain the factors used incalculating the expected environmental concentration. Theconcentration should be provided for each environmentalcompartment (aquatic, terrestrial, atmospheric) expected to beaffected based on the physical and/or chemical characterization ofthe compound of interest. In the majority of cases, the EEC for theaquatic environment would be expected to be significantly less thanthe EIC for the aquatic environment due to dilution. Based ondilution factors for POTWs available from the EPA, applying adilution factor of 10 to the EIC-aquatic to estimate the EEC-aquatic is normally appropriate.

v. Summary

A summary discussion of the environmental fate of the substance(s)of interest should be provided for each environmental compartmentbased on the information and data provided in the EA, and theenvironmental compartment(s) in which the substance is expectedto predominantly amass should be identified. In somecircumstances, transport between environmental compartmentsshould be considered when determining the fate of the substance(s)of interest in the environment.

Aquatic Environment: In general, pharmaceutical substances areexpected to enter predominantly into the aquatic environment and,therefore, the focus of any effects studies most likely will be onaquatic organisms. If the substance(s) of interest rapidly degrades(see section IV.B.1.a.iii) or adsorbs completely and irreversibly to

20

biosolids, then fate and effects in the aquatic environment shouldnot usually be considered.

Terrestrial Environment: In general, substances enter theterrestrial environment predominantly from biosolids removed fromwaste water treatment plants that are subsequently applied to land. Therefore, effects on the terrestrial environment are more likely if acompound adsorbs to biosolids (see section IV.B.1.a.ii). Biosolidsare generally subjected to some form of aerobic or anaerobicdigestion in the waste treatment facility; only a fraction of thebiosolids may be applied to land, while the remainder is incineratedor land filled. Fate and effects testing in the terrestrial environmentshould be considered if testing indicates that the substance(s) ofinterest will significantly adsorb to biosolids (e.g., K $ 1000).oc

Atmospheric Environment: In general, substances that do notadsorb readily to soils, have a high vapor pressure, and have a lowwater solubility, are likely to volatilize significantly from the aquaticor terrestrial environments, although actual volatilization rates willdepend on environmental conditions (e.g., dispersion away from theevaporation site) and on factors that can lessen or enhance theeffective vapor pressure or behavior of the chemical at a liquid-airor solid-air interface. The atmospheric compartment may be ofinterest for medical gases. But, based on the polarity of themajority of compounds at relevant aquatic environmentalconditions, it is unlikely that there would be substantive partitioningfrom the aquatic to the atmospheric environment for otherpharmaceuticals. Any potential for a substance to volatilize andrecycle into the aquatic or terrestrial environments should bediscussed based on the information and data available for thesubstance.

b. Environmental Effects of Released Substances

Tiered approach to environmental effects testing (see below,Microbiological Inhibition Testing through Tier 3 Testing and Figure 1): Ifno rapid, complete depletion mechanism has been identified, it should beassumed that the compound will persist in the environment for some timeand, therefore, the toxicity of the released substances to environmentalorganisms should be evaluated. The fate of the substance should beconsidered when designing the studies. For those compounds that enterthe atmospheric environment, testing should be designed based on theextent to which the substance recycles into the aquatic or terrestrialenvironments. All toxicity test results for the drug or biologic substance

21

should be reported in terms of the quantity and/or concentration of theactive moiety. When using this tiered approach to effects testing, it isimportant to design the test conditions appropriately so that a no-observed-effects concentration is determined.

Microbial Inhibition Testing: A microbial inhibition test or otherappropriate test (e.g., respiration inhibition testing) should be performed toassess the substance(s) of interest's potential to inhibit microorganisms andsubsequently disrupt waste treatment processes.

Assessment Factors: The assessment factors are intended to provide aconsistent regulatory basis for determining when additional ecotoxicitytesting should be performed (tiered approach). They are directly related tothe amount of valid ecotoxicity data available. If the LC or EC or other50 50

appropriate test endpoint divided by the maximum expected environmentalconcentration (MEEC: EIC or EEC, whichever is greater) is less than theassessment factor, additional testing should be performed. The use of EC50

or test end point other than the LC should be limited to those test50

organisms for which the LC is not the test endpoint.50

TEST TIER ASSESSMENT FACTOR

1 1000 (see below)

2 100 (see below)

3 10 (see below)

Alternative scientifically justified approaches also can be used.

Tier 1 Testing: Acute ecotoxicity testing should be performed on aminimum of one suitable test organism (see base set for Tier 2 testing). Ifthe EC or LC divided by the MEEC is greater than or equal to 1000, no50 50

further testing should be conducted unless sublethal effects are observed atthe MEEC. If the EC or LC divided by the MEEC is less than 1000,50 50

Tier 2 testing should be performed. Sublethal effects (observed effects) atthe MEEC indicate that chronic toxicity testing (Tier 3) should beperformed. The use of the assessment factor of 100 could be used for Tier1 testing if there is evidence (e.g., Tier 2 testing on a similar compound) tosupport that the single test organism used would be expected to be themost sensitive of the base set test organisms. If the compound is expectedto partition to both the aquatic and terrestrial environments, usually testingof an aquatic test organism is sufficient since CDER has routinely observedlower toxicity results reported for aquatic test organisms as compared toterrestrial test organisms.

22

Tier 2 Testing: Acute ecotoxicity testing should be performed on theminimum base set of aquatic and/or terrestrial organisms. The aquatic baseset usually consists of (1) a fish acute toxicity test, (2) an aquaticinvertebrate acute toxicity test, and (3) an algal species bioassay. Theterrestrial base set usually consists of (1) plant early growth tests, (2)earthworm toxicity tests, and (3) soil microbial toxicity tests. Usually onlyan earthworm toxicity study is indicated if the substance binds tightly tosoil. A rodent acute toxicity is not included in the terrestrial base set sincethere is usually a significant quantity of mammalian (e.g., mouse, rat, dog,monkey, human) toxicity testing performed, both acute and chronic, tosupport the underlying applicacton and to demonstrate the safety of thedrug or biologic product. Consultation with CDER or CBER is suggestedprior to initiating any terrestrial studies.

If the EC or LC for the most sensitive organism in the base set divided50 50

by the MEEC is greater than or equal to 100, no further testing should beconducted unless sublethal effects are observed at the MEEC. If the EC50

or LC divided by the MEEC is less than 100, Tier 3 testing should be50

performed. Sublethal effects (observed effects) at the MEEC indicate thatchronic toxicity testing (Tier 3) should be performed.

Tier 3 Testing: Chronic toxicity testing should be considered if thecompound has the potential to bioaccumulate or bioconcentrate, ifindicated based on Tier 1 and/or Tier 2 testing, or if there are otherindications that the compound undergoes biotransformation to more toxiccompounds.

Bioaccumulation, or bioconcentration, is a complex, dynamic process that depends on the availability, persistence, and physical and/or chemicalproperties of a compound in the environment. In general, pharmaceuticalstend not to be very lipophilic and are produced and/or used in relativelylow quantities compared to industrial chemicals. In humans, the majorityof pharmaceuticals are metabolized to some extent to SRSs that are morepolar, less toxic, and less pharmacologically active than the parentcompound. This suggests that there is a low potential for bioaccumulationor bioconcentration of pharmaceuticals; however, because of the length oftime it takes to conduct chronic toxicity studies, applicants are encouragedto identify as early as possible compounds that are candidates for thesestudies.

A primary indicator of the potential for bioaccumulation is a compound'soctanol/water partition coefficient (K ). A high octanol/water partitionow

coefficient indicates that the compound will tend to be lipophilic. Chronictoxicity testing should be considered if log K of a compound is greaterow

23

than or equal to 3.5 under relevant environmental conditions (e.g., pH 7),and a justification should be provided if chronic toxicity testing is notperformed. Structural features (e.g., molecular size, polarity) that limitpassage across biological membranes or the lack of bioavailability toenvironmental organisms (e.g., strong adsorption to soil) are mitigatingfactors that could be considered when determining if bioaccumulation(bioconcentration) would be a concern for compounds with a K greaterow

than or equal to 3.5. It may be important to obtain acute toxicity data forthe organism to be tested to set the concentrations for the chronic studiesproperly. If the preparer of an EA is considering initiating chronic toxicitystudies, consultation with CDER or CBER is recommended to ensure thatsuch studies are appropriate and properly designed.

For chronic toxicity testing, if the EC or LC divided by the MEEC is50 50

greater than or equal to 10, no further testing should be conducted unlesssublethal effects are observed at the MEEC. CDER or CBER should beconsulted if the EC or LC divided by the MEEC is less than 10 or there50 50

are sublethal effects at the MEEC.

Test Methods and Test Organisms: Studies should be performed using testorganisms and methods that have been identified by the FDAEnvironmental Assessment Technical Handbook, the EPA (40 CFR 797),the Organization for Economic Cooperation and Development (OECD), orother peer-reviewed literature, as appropriate, for use in environmentalstudies. If the drug or biologic product is intended to act upon anenvironmental organism (e.g., antiparasitic, antibiotic), informationregarding the toxicity to the target organism(s) should be included.

c. Summary

A summary discussion of the environmental fate and effect of thesubstance(s) of interest should be provided. Discussion of the affectedenvironments (aquatic, terrestrial, or atmospheric) should be included. Thetoxicity test results should be compared to the MEEC and the differencebetween the values discussed (e.g., in terms of the assessment factor,> 1000, > 100). It also may be appropriate to relate the toxicity test resultsto other estimated environmental concentrations (see section IV.B.1.a.iv).

2. Use of Fauna or Flora

If an EA is to be submitted for an action because the use of fauna or flora is theenvironmental issue (see section III.C.2 or 3), the EA should include specificinformation regarding the source of the fauna or flora, the mitigation measuresassociated with the harvesting of the resources, and a discussion of the reasonable

24

alternatives.

a. Use of Resources

Information relating to the source of the plant or animal, such as biologicalidentification, government oversight of harvesting, geographic regionwhere biomass is obtained, and harvesting methods and techniques shouldbe included in the EA. The EA should include, but not be limited to, thefollowing types of information:

! Biological identification (i.e., common names, synonyms, variety,species, genus, and family).

! A statement as to whether wild or cultivated specimens are used.

! The geographic region (e.g., country, state, province) wherebiomass is obtained and whether harvesting occurred on public orprivate land.

! A brief description of government oversight of the harvestingincluding, if applicable, the identity of the authority permittingharvesting and identity of authorities consulted regarding theharvesting. Submission of copies of permits or harvestingregulations relating to the specific species is helpful. For speciescovered under CITES, CDER or CBER could request copies ofrelevant permits.

! A brief description of the applicant's oversight of the harvesting.

! A statement indicating whether the species is (1) determined underthe Endangered Species Act or the Convention on InternationalTrade in Endangered Species of Wild Fauna and Flora (CITES) tobe endangered or threatened, (2) entitled to special protectionunder some other Federal law or international treaty to which theUnited States is a party, or (3) the critical habitat of a species thathas been determined to be endangered or threatened under theEndangered Species Act or the Convention on International Tradein Endangered Species of Wild Fauna and Flora (CITES) or isentitled to special protection under some other Federal law orinternational treaty to which the United States is a party.

! A statement describing the part of plant or animal used and whetherit is a renewable resource.

25

! A detailed description of the method of harvest including suchinformation as the type of harvesting (e.g., clear cut, gleaning fromtimber stands destined for clear cutting, salvaging, pruning),frequency of harvest, whether the harvesting technique will affectthe ecosystem (and if so, how), and whether the harvesting isconducted in accordance with government regulations or guidances(include citations to applicable regulations or guidances).

! Bulk weight or other appropriate measure of biomass needed toyield one kilogram of active moiety or biologic substance, theamount that has been harvested to date to support the proposedAgency action for the product, and the amount expected to beharvested in the future.

! The amount of biomass needed to produce the active moiety orbiological substance used to treat the average patient. This shouldbe provided in terms easy to understand (e.g., 2-3 trees per patient). The expected patient population and number of kilograms of activemoiety or biologic substance needed per year should be provided.

! An estimate of the total number of plants or animals in thegeographic region where the biomass is obtained.

! Any uses of the plant or animal other then for the proposed use(humans, food source, habitat for fauna).

! Plant or animal growth rate and/or life span and, if applicable, therate of reproduction/regeneration.

! A discussion of whether the harvesting provides for sustained yield(e.g., percentage of sustainable harvest needed to supply annualneeds based on the proposed use and any prior approved uses).

b. Mitigation Measures

Mitigation measures taken before (e.g., developing a process that uses arenewable part of a plant), during (e.g., limiting/selecting specimens to beharvested), and after harvesting (e.g., reforestation) should be included inthe discussion of mitigation measures (see 40 CFR 1508.20).

26

c. Alternatives to the Proposed Action

A discussion must be provided of the reasonable alternatives that wereconsidered when deciding which biomass source would be used to producethe active moiety or biologic substance (21 CFR 25.40(a)). All alternativesthat were considered (e.g., other species, wild or cultivated sources,chemical synthesis) should be discussed. A brief discussion of the factors(e.g., environmental effects) that were considered in deciding whether ornot the alternative would be used should be provided. The no-action (i.e.,no approval) alternative should also be discussed. It should be indicated ifany of the alternatives not currently used are planned for use in the future.

C. Data Summary Table

To facilitate review, the EA, if appropriate, should include a data summary table in anonconfidential appendix (EA format item 11). Attachment E provides an example of asuitable data summary table.

D. Test Methods and Report Formats

Test methods and report formats are provided in the FDA Environmental AssessmentTechnical Handbook. Equivalent tests, such as those provided by the EPA (40 CFR 796and 797), the Organization for Economic Cooperation and Development (OECD), orother validated, peer-reviewed methods can be used. Environmental fate studies shouldbe compliant with either FDA's current Good Manufacturing Practice (cGMP) regulations(21 CFR 211.194) or FDA's Good Laboratory Practice (GLP) regulations (21 CFR part58). The reports submitted in support of fate testing should include a description of thetest method sufficient for a reviewer to determine the scientific merit of the methodology. Test performance and test reporting for environmental effects studies should meet FDA'sGLP standards. Guidance on test reporting formats is included in the FDA EnvironmentalAssessment Technical Handbook or 40 CFR parts 796 and 797. Raw test data (e.g.,copies of notebook pages, HPLC chromatograms for each assay) should not be includedin the EA.

E. Confidential and Nonconfidential Information

Some of the information that is submitted in an EA may be available elsewhere in anapplication or in a publicly available document. This information may be incorporated byreference in the EA (21 CFR 25.40(d)). However, the EA summary document, thedocument that contains the information recommended in section IV.A, should be a stand-alone document that contains a summary of the public information that is incorporated byreference and, to the extent possible, a summary of the confidential information that iseither incorporated by reference or included in confidential appendices to the EA (21 CFR25.51(a)). The EA will be made public by the FDA as required by regulations issued by

27

the Council on Environmental Quality. Therefore, the EA should contain, if appropriate,three distinct parts: (1) the EA summary document (see section IV.A), which isnonconfidential; (2) nonconfidential appendices; and (3) appendices with confidentialinformation used to support the EA. Confidential data and information pertinent to theenvironmental review of a proposed action should be included in confidential appendiceswhenever possible to facilitate review of the EA. All confidential appendices should be atthe end of the environmental assessment document. References to nonconfidential andconfidential appendices may be included in the EA summary document, as appropriate. The EA summary document, nonconfidential appendices, and FONSI are made availablefor public inspection to the extent allowed by applicable laws (21 CFR 25.50(a) and (b)).

Attachment F provides general guidance as to which information can be included inconfidential appendices of the EA. It is the applicant's responsibility to clearly identify theinformation in the EA that it believes is confidential.

F. Master Files for Drugs and Biologics

CDER and CBER do not take action on drug master files (DMFs) or master files (MFs) (i.e., they do not approve or disapprove submissions to a DMF (21 CFR 314.420(a)) orMF). Therefore, NEPA does not apply, and no EA needs to be submitted for a masterfile.

However, if an EA is required for the particular application, certain information that isincluded in a master file may be needed to address the relevant environmental issue(s). Inthese instances, the applicant seeking marketing approval should include thenonconfidential information in the EA summary document, rather than provide referenceto the master file. The master file holder may be the applicant or an independentmanufacturer who wants to limit the applicant's access to proprietary information. Amaster file reference may be provided for the confidential information, although thisinformation must be summarized to the extent possible and included in the EA for publicrelease. To expedite review of the EA, CDER and CBER prefer that copies ofconfidential information from master files be submitted in confidential appendices to theEA, whenever possible. If a letter of authorization is provided to reference confidentialinformation in a master file, the specific type of information that is being referenced, thesubmission date, and page number where the information can be located should be stated. References to master files should be included in a confidential appendix since suchreferences are considered confidential commercial information under the Freedom ofInformation Act (FOIA).

28

REFERENCES

1. FDA, "National Environmental Policy Act; Revision of Policies and Procedures; FinalRule," Federal Register, July 29, 1997 (62 FR 40569).

2. FDA, "National Environmental Policy Act; Proposed Revision of Policies and Procedures;Proposed Rule," Federal Register, April 3, 1996 (61 FR 14922); (republished May 1,1996 (61 FR 19476)).

3. Rand, G., and S. Petrocelli, Fundamentals of Aquatic Toxicology, Hemisphere PublishingCorporation, 1987.

4. Zeeman, M., and J. Gilford, "Ecological Hazard Evaluation and Risk Assessment UnderEPA's Toxic Substances Control Act (TSCA): An Introduction," EnvironmentalToxicology and Risk Assessment, ASTM STP 1179, Wayne G. Landis, Jane S. Hughes,and Michael A. Lewis, Eds., American Society for Testing and Materials, Philadelphia:1993, pp. 7-21.

In context of Attachments A and B, substitute directly means that the drug or biologic product (i.e., active4

moiety or biologic substance) will be used for the same indication, at the same or lower dosage levels (i.e., total dailydose), and for the same or shorter duration of use (e.g., number of days) as previously approved by the Agency for thesame active moiety or biologic substance.

29

ATTACHMENT A: NO INCREASED USE

The following are types of actions that are not considered to result in increased use of an activemoiety if approved by the Agency:

! Chemistry, manufacturing and control supplements (§§ 314.70, 601.12).

! Abbreviated applications.

! Lower doses than previously approved for the same indication (i.e., total daily dose).

! Shorter duration of use than previously approved for the same indication (e.g., number ofdays).

! Exclusion of a patient population in the labeling (e.g., by age, gender, complicatingmedical conditions).

! A prodrug for which the active metabolite is an approved product in the United States andwhich is intended to substitute directly for that approved product. An active moiety4

which is the active metabolite of an approved prodrug in the United States would beconsidered similarly.

! New dosage forms that substitute directly for an approved product.

! Product reformulations in which the labeled amount of active moiety/biologic substanceremains constant.

! Packaging changes/dosage form product line extensions that substitute directly for an approved product (e.g., new delivery system, addition of a different vial fill size).

! Combination drugs in which the single product substitutes directly for two approvedproducts that would be administered separately.

30

ATTACHMENT B: INCREASED USE

The following are types of actions that are considered to result in increased use of an activemoiety if approved by the Agency:

! New molecular entities.

! A new indication for a drug that was previously approved. This includes those actionsrequesting approval of off-label uses and switches from a second-line to first-lineindication.

! L to OTC switches.

! Higher doses than were previously approved (i.e., total daily dose).

! Longer duration of use than previously approved (e.g., number of days).

! Inclusion of a patient population in the labeling that had previously been specificallyexcluded (e.g., by age, gender, complicating medical conditions).

! New dosage forms/routes of administration that increase the amount of activeingredient/biologic substance used. For example, the use of the active moiety or biologicsubstance for the same indication will normally increase if a switch is made from aninjectable dosage form to an oral dosage form.

31

ATTACHMENT C: 40 CFR 1508.27

§ 1508.27 Significantly.

"Significantly" as used in NEPA requires considerations of both context and intensity:

(a) Context. This means that the significance of an action must be analyzed in several contextssuch as society as a whole (human, national), the affected region, the affected interests, and thelocality. Significance varies with the setting of the proposed action. For instance, in the case of asite-specific action, significance would usually depend upon the effects in the locale rather than inthe world as a whole. Both short- and long-term effects are relevant.

(b) Intensity. This refers to the severity of impact. Responsible officials must bear in mind thatmore than one agency may make decisions about partial aspects of a major action. The followingshould be considered in evaluating intensity:

(1) Impacts that may be both beneficial and adverse. A significant effect may exist even if theFederal agency believes that on balance the effect will be beneficial.

(2) The degree to which the proposed action affects public health or safety.

(3) Unique characteristics of the geographic area such as proximity to historic or culturalresources, park lands, prime farmlands, wetlands, wild and scenic rivers, or ecologicallycritical areas.

(4) The degree to which the effects on the quality of the human environment are likely to behighly controversial.

(5) The degree to which the possible effects on the quality of the human environment arehighly uncertain or involve unique or unknown risks.

(6) The degree to which the action may establish a precedent for future actions withsignificant effects or represents a decision in principle about a future consideration.

(7) Whether the action is related to other actions with individually insignificant butcumulatively significant impacts. Significance exists if it is reasonable to anticipate acumulatively significant impact on the environment. Significance cannot be avoided byterming an action temporary or by breaking it down into small component parts.

(8) The degree to which the action may adversely affect districts, sites, highways, structures,or objects listed in or eligible for listing in the National Register of Historic Places or maycause loss or destruction of significant scientific, cultural, or historical resources.

(9) The degree to which the action may adversely affect an endangered or threatened speciesor its habitat that has been determined to be critical under the Endangered Species Act of1973.

(10) Whether the action threatens a violation of Federal, State, or local law or requirementsimposed for the protection of the environment.

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ATTACHMENT D: EA FORMAT

1. Date2. Name of Applicant/Petitioner3. Address4. Description of Proposed Action

a. Requested Approvalb. Need for Actionc. Locations of Used. Disposal Sites

5. Identification of Substances that are the Subject of the Proposed Actiona. Nomenclature

i. Established Name (U.S. Adopted Name - USAN)ii. Brand/Proprietary Name/Tradenameiii. Chemical Names or Genus/Species of Biologic Product (e.g., virus)

!! Chemical Abstracts (CA) Index Name!! Systematic Chemical Name

b. Chemical Abstracts Service (CAS) Registration Numberc. Molecular Formulad. Molecular Weighte. Structural (graphic) Formula/Amino Acid Sequence

6. Environmental Issues7. Mitigation Measures8. Alternatives to the Proposed Action9. List of Preparers10. References11. Appendices

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ATTACHMENT E: SAMPLE DATA SUMMARY TABLE

SAMPLE DATA SUMMARY TABLE

PHYSICAL/CHEMICAL CHARACTERIZATION

Water Solubility1

Dissociation Constant(s)

Log Octanol/Water Partition Coefficient (LogK )ow

1

Vapor Pressure or Henry's Law Constant

Sorption/Desorption (K )oc1

DEPLETION MECHANISMS

Hydrolysis

Aerobic Biodegradation

Soil Biodegradation

Photolysis

Metabolism

ENVIRONMENTAL EFFECTS 2

Microbial Inhibition

Acute Toxicity

Chronic Toxicity

Depending on dissociations constant(s), water solubility and octanol/water partition coefficient may have to be1

determined at pH 5 and 9, in addition to pH 7 or K may have to be determined in acidic and/or alkaline soil in additionoc

to neutral soil. See section IV.B.1.a.ii for guidance.

Identify organism(s) and report results, e.g., NOEC, MIC, EC LC in ppm of active moiety.250, 50

34

ATTACHMENT F: CONFIDENTIAL/NONCONFIDENTIAL

EA FORMAT ITEM SUBSECTION NONCONFIDENTIAL CONFIDENTIAL

1.Date *** X

2. Name of *** XApplicant/Petitioner

3. Address *** X

4. Description of a. Requested Approval XProposed Action

b. Need for Action X

c. Locations of Use X

d. Disposal Sites X

5. Identification of a. Nomenclature XSubstances that are theSubject of theProposed Action

b. CAS Number X

c. Molecular Formula X

d. Molecular Weight X

e. Structural Formula X

EA FORMAT ITEM SUBSECTION NONCONFIDENTIAL CONFIDENTIAL

35

6. Environmental a. Assessing Toxicity to For example: For example:Issue Environmental Organisms

(Specific exist in the environment. pharmacological activity data forenvironmental issues * Summary discussion of SRSsidentified in section toxicity/activity of predominant * Test reportsIV.B) SRSs relative to the parent * Environmental concentration

* Substances expected to enter or * Specific toxicology/

(active) compound estimates* Test results physical/chemical

characterization* Method of calculating estimates of

environmental concentration* Supporting information for

spatial/temporal depletion factors* Environmental effects test results

b. Use of Fauna or Flora For example: For example:

* Biological identification and other * Bulk weight of biomass neededinformation relating to species to produce a kg of active moietyused (e.g., plant growth rate) * Amount harvested

* Geographic region of the source * The expected patient population* Government oversight and kg of active moiety expected* Method of harvesting to be used per year

7. Mitigation *** XMeasures

8. Alternatives to the *** XProposed Action

9. List of Preparers *** X

EA FORMAT ITEM SUBSECTION NONCONFIDENTIAL CONFIDENTIAL

36

10. References *** X

11. Appendices *** For example: For example:

* Referenced articles not generally * Estimates of the kg of activeavailable or which are used to moiety to be used/yearsupport specific claims in the EA * Test reportsdocument * Letters of authorization to DMFs

* Data summary table

37

ATTACHMENT G: GLOSSARY OF TERMS

Active Moiety: The molecule or ion, excluding those appended portions of the molecule thatcause the drug to be an ester, salt (including a salt with hydrogen or coordination bonds), or othernoncovalent derivative (such as a complex, chelate, or clathrate) of the molecule, responsible forthe physiological or pharmacological action of the drug substance (21 CFR 314.108(a)). Theactive moiety is the entire molecule or ion, not the "active site."

Bioaccumulation: The process by which industrial waste, chemicals, and other substancesgradually accumulate in living tissue.

Bioconcentration: The process by which industrial waste, chemicals, and other substancesaccumulate directly from water into and onto aquatic organisms.

Biological (biologic) product: Any virus, therapeutic serum, toxin, antitoxin, vaccine, blood,blood component, derivative, allergenic product, or analogous product applicable to theprevention, treatment, or cure of a disease or condition of human beings (section 351 of thePublic Health Service Act).

Biomass: The plant, plant part (e.g., bark, leaves, flower, seed), animal, or animal part (e.g.,skin, liver, stomach) that is collected for processing into a drug or biologic.

Drug product: A finished dosage form, for example, tablet, capsule, or solution, that contains adrug substance, generally, but not necessarily, in association with one or more ingredients (21CFR 314.3(b)).

Drug substance: An active ingredient that is intended to furnish pharmacological activity orother direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or toaffect the structure or any function of the human body, but does not include intermediates used inthe synthesis of such ingredient (21 CFR 314.3(b)).

Expected environmental concentration (EEC): The expected concentration of the activemoiety or other structurally related substance of interest that organisms would be exposed to inthe environment (e.g., surface water) after consideration of spatial or temporal concentration ordepletion factors such as dilution, degradation, sorption, bioaccumulation. This is sometimesreferred to as the predicted environmental concentration (PEC).

Expected introduction concentration (EIC) for disposal: The expected introductionconcentration of the active moiety that may enter the environment due to disposal. Depletionmechanisms that occur prior to introduction into the environment may be considered in thecalculation as indicated in the text.

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Expected introduction concentration (EIC) for use: The expected introduction concentration,based on fifth-year marketing estimates, of the active moiety that can enter the environment dueto use. Depletion mechanisms that occur prior to introduction into the environment and humanmetabolism may be considered in the calculation as indicated in the text.

Half-life (t ): Time required to reduce by one-half the concentration of a material.½

Lowest observed effect concentration (LOEC): The lowest concentration of a material used ina toxicity test that has a statistically significant adverse effect on the exposed population of thetest organisms as compared with the controls.

Master file: A submission of information to the FDA by a person who intends it to be referencedduring the review of an application. See 21 CFR 314.420 for specific information on drug masterfiles.

Maximum expected environmental concentration (MEEC): The expected introductionconcentration (EIC) or expected environmental concentration (EEC), whichever is greater.

Median effective concentration (EC ): The concentration of material to which organisms are50

exposed that is estimated to be effective in producing some sublethal response in 50 percent of thetest organisms. The EC is usually expressed as a time-dependent variable (e.g., 24 hour EC ).50 50

Median lethal concentration (LC ): The concentration of material to which organisms are50

exposed that is estimated to be lethal to 50 percent of the test organisms. The LC is usually50

expressed as a time-dependent variable (e.g., 24 hour LC ).50

Minimum inhibitory concentration (MIC): The lowest concentration of a chemical thatinhibits the visible growth of the test organisms.

New molecular entity: An active moiety (present as the unmodified base [parent] compound, oran ester or a salt, clathrate, or other noncovalent derivative of the base [parent] compound) thathas not been previously approved or marketed as the active moiety in the United States for use ina drug product, either as a single ingredient or as part of a combination product, or as part of amixture of stereoisomers.

No observed effect concentration (NOEC): The highest concentration of a material used in atoxicity test that has no statistically significant adverse effect on the exposed population of testorganisms as compared with the controls.

Octanol/water partition coefficient (K ): The ratio of a chemical's solubility in n-octanol andow

water at equilibrium; also expressed as P. A measurement of a drug's or biologic's lipophilicityand an indication of its ability to cross cell membranes. The logarithm of P or K is used as anow

estimate of the tendency of the chemical to bioaccumulate or adsorb to soil or sediments.

39

Parts per billion (ppb): One unit of chemical (usually expressed as mass) per 1,000,000,000(10 ) units of medium (e.g., water) or organism (e.g., tissue) in which it is contained. For water 19

µg/L = 1 ppb; for tissue 1 µg/kg = 1 ng/g = 1 ppb.

Parts per million (ppm): One unit of chemical (usually expressed as mass) per 1,000,000 (10 )6

units of medium (e.g., water) or organism (e.g., tissue) in which it is contained. For water 1 mg/L= 1 ppm; for tissue 1 mg/kg = 1 µg/g = 1 ppm.

Parts per trillion (pptr): One unit of chemical (usually expressed as mass) per1,000,000,000,000 (10 ) units of medium (e.g., water) or organism (e.g., tissue) in which it is12

contained. For water 1 ng/L = 1 pptr; for tissue 1 ng/kg = 1 pptr.

Soil or sediment/water partition coefficient (K ): The ratio of chemical adsorbed per unitoc

weight of organic carbon in soil or sediment to the concentration of the chemical in solution atequilibrium.

Toxicity: The inherent potential or capacity of a material to cause adverse effects in a livingorganism.